Type 2 Transglutaminase, mitochondria and Huntington's disease: Menage a trois

• TG2 regulates the switch between mitochondria respiration and glycolysis.
• TG2 is involved in the core machinery regulating the fission/fusion of mitochondria and their clearance by autophagy.
• In cells lacking TG2 and expressing mutated Huntingtin there is drastic reduction of IF1 protein.

Mitochondria produce the bulk of cellular energy and work as decisional “hubs” for cellular responses by integrating different input signals. The determinant in the physiopathology of mammals, they attract major attention, nowadays, for their contribution to brain degeneration. How they can withstand or succumb to insults leading to neuronal death is an object of great attention increasing the need for a better understanding of the interplay between inner and outer mitochondrial pathways residing in the cytosol. Of the latter, those dictating protein metabolism and therefore influencing the quality function and control of the organelle are of our most immediate interest and here we describe the Transglutaminase type 2 (TG2) contribution to mitochondrial function, dysfunction and neurodegeneration. Besides reviewing the latest evidences we share also the novel ones on the IF1 pathway depicting a molecular conduit governing mitochondrial turnover and homeostasis relevant to envisaging preventive and therapeutic strategies to respectively predict and counteract deficiencies associated with deregulated mitochondrial function in neuropathology.